EP0579840A1 - Analogues de vitamine d 3? contenant du fluor. - Google Patents

Analogues de vitamine d 3? contenant du fluor.

Info

Publication number
EP0579840A1
EP0579840A1 EP93902528A EP93902528A EP0579840A1 EP 0579840 A1 EP0579840 A1 EP 0579840A1 EP 93902528 A EP93902528 A EP 93902528A EP 93902528 A EP93902528 A EP 93902528A EP 0579840 A1 EP0579840 A1 EP 0579840A1
Authority
EP
European Patent Office
Prior art keywords
compound
reference example
vitamin
protecting group
acetyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP93902528A
Other languages
German (de)
English (en)
Other versions
EP0579840B1 (fr
Inventor
Nobuo - - Kichijojihig Ikekawa
Takeo - - - Minamiosaw Taguchi
Yoko Tanaka
Yoshiro - - Udagawa- Kobayashi
Yutaka Miyukigaoka Ohira
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daikin Industries Ltd
Original Assignee
Daikin Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daikin Industries Ltd filed Critical Daikin Industries Ltd
Publication of EP0579840A1 publication Critical patent/EP0579840A1/fr
Application granted granted Critical
Publication of EP0579840B1 publication Critical patent/EP0579840B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/48—Halogenated derivatives
    • C07C35/52—Alcohols with a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to novel fluorine-containing vitamin Do analogues which have excellent pharmacological activities, such as tumor cell differentiation-inducing activity and are expected to be used as a medicament.
  • active-type vitamin D3 a bio-metabolite of vitamin D 3 , l ⁇ ,25-dihydroxyvitamin D3
  • active-type vitamin D3 has an activity of promoting absorption of calcium via intestinal tract and thereby is useful as a medicament for the treatment of bone diseases.
  • active-type vitamin D and analogues thereof have a differentiation-inducing activity for recovering normal cells from cancerated cells (cf. Hirobu i Tanaka et al., "Seikagaku” (Biochemistry), Vol. 55, 1323, 1983) and further that some of these compounds have a remarked activity of inhibiting the progress of cancer (K. . Colton et al., Lancet, Jan. ⁇ 8, 188, 1989).
  • the present inventors have intensively studied as to novel fluorine-containing vitamin D 3 analogues which have excellent cell differentiation-inducing activity as well as high selectivity in calcium metabolism with less side effects, i.e. inhiDition of hepercalcaemia .
  • An object of the invention is to provide novel fluorine-containing vitamin D3 analogues having pharmacological activities, especially anti-tumor activity owing tc the cell differentiation-inducing activity.
  • a further object of the invention is to provide a novel intermediate suitable for the preparation of the active fluorine-containing vitamin D3 analogues.
  • the fluorine-containing vitamin D 3 analogues of this -invention have the following formula [I]:
  • R- ⁇ , R ⁇ and R J are independently hydrogen atom or a hydroxy-protecting group.
  • the hydroxy-protecting group includes a group being capable of forming acetal type protecting group (e.g. methoxymethyl, ethoxyethyl, methoxyethoxymethyl, tetrahydropyranyl, etc.), a silyl ether type protecting group (e.g. trimethylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, etc.), an acyl group (e.g. acetyl), and the like.
  • acetal type protecting group e.g. methoxymethyl, ethoxyethyl, methoxyethoxymethyl, tetrahydropyranyl, etc.
  • silyl ether type protecting group e.g. trimethylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl
  • the compounds [I] of this invention can be prepared by various processes. One of the best processes is illustrated below.
  • R is a hydroxy-protecting group
  • R 7 and R3 are each a hydroxy-protecting group
  • Ph means phenyl, to give a condensed product of the formula [I] of this invention.
  • the above coupling reaction of the compound [II] and the compound [III] is usually carried out at a low temperature, for example -100°C to -50°C, preferably -78°C to -20°C, in an ether solvent (e.g. diethyl ether, tetra- hydrofuran (THF), etc.).
  • the conversion of the [ring A] fragment into the corresponding carbanion is carried out by treating the fragment with an appropriate base such as an alkyl-lithium (e.g. n-butyllithium, etc).
  • the reaction time is for 10 minutes to 24 hours, preferably for 30 minutes to 2 hours.
  • the obtained product [I] can be purified by a conventional method, for example, by silica gel column chromatograph .
  • the removal of the hydroxy-protecting group from the compound [I] can optionally be carried out by a conventional method.
  • R and R are each a hydroxy-protecting group, and MOM means methoxymethyl group.
  • the starting compound [II] ([II-l] and [II-2]) can be prepared by reacting the aldehyde compound (1) with the bromide compound
  • R4 is acetyl and compound [III] wherein R 7 and R ⁇ are t- butyldimethylsilyl:
  • Example 1-1 The silyl compound obtained in Example 1-1 (99 mg) is added to a suspension of ion-exchange resin (50 , 3 g) in methanol (30 ml) and stirred for 24 hours at room temperature. After filtering the solution and distilling off the solvent, the residue is purified by column chromatography to give the desired compound (A) (66 mg) .
  • Subculture cells derived from human colonic cancer were inoculated onto a 24-well plate for tissue culture and was cultured in RPMI-1640 medium (added with 10 % fetal calf serum). After culturing for about 24 hours, the supernatant was removed. To the residue was added a medium containing 2 x 10 — J 3M sodium butyrate and the test compound as mentioned below (exchange of the medium), and the mixture was subjected to station culture in a culture vessel containing carbon dioxide (5 I C0 2 - 95 % air) at
  • _ cells were treated by 2 x 10 ⁇ sodium butyrate and the compounds of this invention, the cells were differentiated into mucin-producing cells.
  • Vitamin D- defficient rats were prepared and the calcium concentration in serum was measured.
  • Wistar rats (5 rats per each group) was fed with vitamin D-free, low calcium (0.02 %) feed for about 3 weeks.
  • the test compound (650 pmole) solubilized in solvent (95 % propylene glycol + 5 % ethanol) was subcutaneously injected at the behind of the rats in a dose of 0.1 ml per day. In a control group, only the solvent was injected lilkewise. Three and four days after the first injection, the blood was taken and the calcium concentration in the serum was measured, and the obtained data were shown in the average thereof.
  • Test compounds The same as used in the above Experiment 1.
  • Test compouds Increase of serum calcium concentration* (mg/dl) l ,25-dihydroxyvitamin D3 3.1 ⁇ 0.6

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Analogues de vitamine D3 contenant du fluor, répondant à la formule (I), dans laquelle R1, R2 et R3 représentent indépendamment un atome d'hydrogène, un groupe protecteur d'hydroxy, et présentant d'excellentes activités pharmacologiques, par exemple une activité d'induction de la différenciation cellulaire. Ces analogues sont utilisables comme médicament.
EP93902528A 1992-02-10 1993-01-26 Analogues de vitamine d3 contenant du fluor Expired - Lifetime EP0579840B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US07/832,888 US5200536A (en) 1992-02-10 1992-02-10 Fluorine-containing vitamin D3 analogues
US832888 1992-02-10
PCT/JP1993/000088 WO1993016040A1 (fr) 1992-02-10 1993-01-26 Analogues de vitamine d3 contenant du fluor

Publications (2)

Publication Number Publication Date
EP0579840A1 true EP0579840A1 (fr) 1994-01-26
EP0579840B1 EP0579840B1 (fr) 1995-08-09

Family

ID=25262860

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93902528A Expired - Lifetime EP0579840B1 (fr) 1992-02-10 1993-01-26 Analogues de vitamine d3 contenant du fluor

Country Status (7)

Country Link
US (1) US5200536A (fr)
EP (1) EP0579840B1 (fr)
JP (1) JP2658574B2 (fr)
CA (1) CA2107471C (fr)
DE (1) DE69300355T2 (fr)
HU (1) HUT65350A (fr)
WO (1) WO1993016040A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9017890D0 (en) * 1990-08-15 1990-09-26 Leo Pharm Prod Ltd Chemical compounds i
US20040009958A1 (en) * 1991-01-08 2004-01-15 Bone Care International, Inc. Methods for preparation and use of 1alpha,24(S)-dihydroxyvitamin D2
IL99368A (en) * 1991-09-02 1996-01-19 Teva Pharma Preparations for the treatment of psoriasis and atopic dermatitis, which contain the result of xanthine
DE4220757A1 (de) * 1992-06-24 1994-01-05 Schering Ag Derivate in der Vitamin D-Reihe mit Modifikationen in der 20-Position, Verfahren zu ihrer Herstellung, Zwischenprodukte für dieses Verfahren, diese Derivate enthaltende pharmazeutische Präparate sowie deren Verwendung zur Herstellung von Arzneimitteln
DE4221961A1 (de) * 1992-06-30 1994-01-05 Schering Ag 22-En-25-oxa-Derivate in der Vitamin D-Reihe, Verfahren zu ihrer Herstellung, diese Derivate enthaltenen pharmazeutische Präparate sowie deren Verwendung als Arzneimittel
DK0665221T3 (da) * 1992-10-16 2000-06-05 Chugai Pharmaceutical Co Ltd Vitamin D derivat og fremgangsmåde til fremstilling af dette
GB9223061D0 (en) * 1992-11-04 1992-12-16 Leo Pharm Prod Ltd Chemical compounds
US5401733A (en) * 1993-10-01 1995-03-28 Hoffmann-La Roche Inc. Stable and active metabolites of 1,25-dihydroxy-16-ene-cholecalciferol
NO971934L (no) * 1996-05-23 1997-11-24 Hoffmann La Roche Flourinerte vitamin D3 -analoger
WO2003026445A1 (fr) * 2001-09-27 2003-04-03 The Coca-Cola Company Vitaminisation de produits alimentaires

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4804502A (en) * 1988-01-20 1989-02-14 Hoffmann-La Roche Inc. Vitamin D compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9316040A1 *

Also Published As

Publication number Publication date
CA2107471A1 (fr) 1993-08-11
EP0579840B1 (fr) 1995-08-09
JP2658574B2 (ja) 1997-09-30
HU9302847D0 (en) 1993-12-28
HUT65350A (en) 1994-05-02
CA2107471C (fr) 2002-10-29
DE69300355T2 (de) 1996-01-25
WO1993016040A1 (fr) 1993-08-19
US5200536A (en) 1993-04-06
DE69300355D1 (de) 1995-09-14
JPH07508501A (ja) 1995-09-21

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